This Week's Citation Classic

This week's citation classic is Avery OT, MacLeod CM & McCarty M. 1944. Studies on the chemical nature of the substance inducing transformation of pneumonococcal types: induction of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III. Journal of Experimental Medicine 79: 137-158.

From the time scientists began thinking about the physical nature of the genetic material, the leading candidate was protein. Nucleic acid, first discovered by Frederick Miescher in 1869, was well known, but was considered too regular, too monotonous to encode something as fantastic as life itself. Nucleic acid was thought instead to be a structural molecule, like scaffolding. Protein, by contrast, was known to be considerably complex, hence was thought to be the information bearing molecule.

Avery and colleagues changed all that. Through a simple and ingenious set of experiments, Avery demonstrated unequivocally that DNA was the genetic material. The Dolan DNA Learning Center, Cold Spring Harbor Laboratory has a marvelous animation sequence describing the actual experiments.

The paper itself is a tour de force model of clarity. Unlike many of today's papers, it reads something like a mystery novel where the clues accumulate until there is no choice but to be borne along inexorably towards an exciting conclusion.

"The data obtained by chemical, enzymatic, and serological analyses together with the results of preliminary studies by electrophoresis, ultracentrifugation, and ultraviolet spectroscopy indicate that, within the limits of the methods, the active fraction contains no demonstrable protein, unbound lipid, or serologically reactive polysaccharide and consists principally, if not solely, of a highly polymerized, viscous form of desoxyribonucleic acid.... The evidence presented supports the belief that a nucleic acid of the desoxyribose type is the fundamental unit of the transforming principle of Pneumococcus Type III."

However, it was some time before Avery et al.'s results were generally accepted. Some scientists thought there must have been contamination; others thought it was a neat trick, but specific just to Pneumoncoccus.

Horace Freeland Judson, author of the Eighth Day of Creation, wrote "some papers are great, of course, because they establish, define, settle their issues. This great paper did something else: Avery opened a new space in biologists' minds--a space that his conclusions, so carefully hedged, could not at once fill up."

Not everyone was resistant to the notion of DNA as the genetic material. Chargaff immediately changed fields upon reading Avery et al. 1944, and went on to make important discoveries on the ratios of the various bases. Hershey and Chase were convinced. Watson and Crick obviously spent little time worrying whether the transforming principle was protein or DNA.

One of the great travesties of 20th century science is that Avery, MacLeod and McCarty did not receive the Nobel Prize for their achievement. No less a giant than Joshua Lederberg claimed that theirs was "(t)he pivotal discovery of 20th-century biology."

There's a nice collection of documents at the National Library of Medicine.

Avery during a lighter moment...Photos from National Library of Medicine.